Chicago, IL (UroToday.com) While the introduction of targeted therapies for the management of metastatic renal cell carcinoma drastically changed the landscape, they ultimately have been unable to provide a cure for patients (pts) with advanced renal cell carcinoma (aRCC). By providing progression-free survival (PFS), they have remained the mainstay of therapy for aRCC.

However, as immune checkpoint blockage (ICB) has become more prominent in the management of other solid malignancies, there is interest in their utilization in the management of RCC. With a high mutational load, there is sufficient rationale to suggest potential benefit.

By combining the antiangiogenic properties of the traditional targeted therapies with immune checkpoint blockade, the authors suggest potential improved outcomes in patients with aRCC.

Dr. Choueiri gave a very nice presentation of these early results. As a reminder, the objective response rate (ORR) of axitinib as 2nd line monotherapy was 19.4% (PFS 6.7 month), while as high as 32% in treatment naïve metastatic RCC patients (PFS 10.1 months).

The JAVELIN Renal 100 (NCT02493751) is a phase Ib open-label, multi-center, multiple-dose trial evaluating safety and clinical activity of avelumab (a PD-L1 antibody) and axitinib (VEGF receptor inhibitor) in treatment-naïve pts with aRCC. In this abstract, the authors provide updated results. Again, this is primarily a phase 1b trial with a focus on safety and clinical activity.

Study Design: The patients included in this study were treatment-naïve, healthy (ECOG PS ≤1) patients with advanced clear-cell aRCC, ≥1 measurable metastatic lesion, and a fresh or archival tumor specimen. The primary tumor must have been resected already. Patients received avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID until progression, unacceptable toxicity, or withdrawal. Endpoints included safety (NCI CTCAE v4.03) and objective response (RECIST v1.1).- In the dose-finding phase, there was a 5 mg bid axitinib 7-day lead-in period followed by avelumab initiation (to assess effect on axitinib pharmacokinetics)- In the dose-expansion phase, some patients were treated with the lead-in schedule while others were treated with both simultaneously.PDL-1 status was assessed using Ventana SP263 assay.

By the time of publication, they had reached their enrollment goal of 55 patients (median age 60.0 yrs old; 76.4% male; 34.5% ECOG PS = 1; equal mix of favorable and unfavorable MSKCC stratification).

At this time, 55 patients had received axitinib (median time of treatment with axitinib was 34.0 weeks) while only 54 had received avelumab (median time of treatment 36.5 weeks). Treatment ongoing in 30-31 patients. Dose adjustment (escalation or reduction) was required in 41 patients receiving axitinib.

In terms of clinical response, 32 patients (58.2%) had a confirmed ORR, with one additional patient ongoing treatment who has an unconfirmed response. This includes 3 complete responses and 29 partial responses. On a swimmer’s plot, early response was noted in most of these 32 patients with durable response (24 have ongoing response). There were no deaths in the 32 patients who responded. 34 patients experienced tumor shrinkage >= 30%.

When related to PDL-1 status, for which they assessed many different cutoffs (1-5%), the best discrimination was found using a cutoff of 1% as PDL-1 positive. Patients who were PDL-1+ (1% cutoff) were 3.38x more likely to have an ORR.

In terms of safety profile, which was the primary objective, ~62% of patients had Grade 3-5 treatment related adverse events. There was one immune related TRAE due to myocarditis, likely due to the avelumab. However, most of the Grade 3 TRAEs were typical of TKI therapu.

Based on this, the authors conclude that the adverse event rate of the combination of avelumab + axitinib appears consistent to when they are administered as monotherapy, and not causing additive effects. They seem encouraged by early antitumor activity.

This is merely preliminary phase 1b results. Further phase II and phase III trials and longer follow-up of the current patients are need to better assess oncologic outcomes prior to use. In fact, an ongoing Phase III trial (NCT02685006) is investigating the efficacy of this combination against sunitinib in treatment naive clear cell RCC patients.

Discussion Points:Targeted therapies, as a class, have significant toxicity. Adjuvant therapy for aRCC is not yet recommended due to the lack of oncologic benefit and high AE rate. As such, the oncologic benefit of adding ICB to targeted therapies must be clearly evident to warrant treating patients with such toxic combinations. This combination appears to have significant promise, and we look forward to phase III results.

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